The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index; 1 of the 34 sources its claims cite were checked for support.
Abandoning M1/M2 for a Network Model of Macrophage Function
Open accessOverview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
15 Own interpretation · 13 Not checked yet · 7 No basis given · 3 Check pending · 3 No full text of the sources · 1 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Gordon showed that IL-4, the prototypical Th2 cytokine, augments expression of the mannose receptor on peritoneal macrophages without inducing TNFα production.”
What the sources say
- Partly supportedcites [38] Stein M Keshav S Harris N Gordon S Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 1992 176 287 292 1613462 PMC2119288 sourceExperimental — accuracy not yet measured
The Summary (p. 287) reports that IL-4 increased mannose-receptor surface expression in elicited peritoneal macrophages and did not markedly increase TNFα mRNA. It describes reduced proinflammatory cytokine secretion, but the cited result measures TNFα mRNA rather than TNFα protein production, so that part of the claim is not directly established. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“More likely, cells augment or attenuate certain markers considered M1 or M2 in parallel (i.e., the same macrophages express NOS and Arg1).”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“After myocardial infarction (MI), macrophage numbers increase in the heart through the combined effects of massive recruitment of bone marrow-derived cells and local self-renewal1, 3.”
What the sources say
- Not checked yetcites [1] Heidt T Courties G Dutta P Sager HB Sebas M Iwamoto Y Sun Y Da Silva N Panizzi P van der Laan AM Swirski FK Weissleder R Nahrendorf M Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res 2014 115 284 295 24786973 PMC4082439 source
- Check pendingcites [3] Hilgendorf I Gerhardt LM Tan TC Winter C Holderried TA Chousterman BG Iwamoto Y Liao R Zirlik A Scherer-Crosbie M Hedrick CC Libby P Nahrendorf M Weissleder R Swirski FK Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res 2014 114 1611 1622 24625784 PMC4017349 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We can avoid this by thinking about macrophage functions as belonging to a network that accommodates for macrophage origins (monocyte- vs. locally-derived tissue residents); environmental stimuli (different organs, different stimuli during steady state and inflammation) and time (development, stages of inflammation, aging).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For one, the concept is an in vitro construction that relies on stimulating macrophages in culture with a defined set of factors.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In other words, a macrophage encountering a stimulus relevant to cardiovascular disease produces mediators that lie outside the M1/M2 “spectrum”.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A check of a cited source is scheduled, or we don’t hold its full text yet; the claim is checked once it runs.
In the paper
“We now know that, in the steady state, arterial24 and cardiac1, 25–27 macrophages are mostly independent of monocytes”
What the sources say
- Not checked — no full text of the sourcecites [24] Ensan S Li A Besla R Degousee N Cosme J Roufaiel M Shikatani EA El-Maklizi M Williams JW Robins L Li C Lewis B Yun TJ Lee JS Wieghofer P Khattar R Farrokhi K Byrne J Ouzounian M Zavitz CC Levy GA Bauer CM Libby P Husain M Swirski FK Cheong C Prinz M Hilgendorf I Randolph GJ Epelman S Gramolini AO Cybulsky MI Rubin BB Robbins CS Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat Immunol 2016 17 159 168 26642357 source
- Not checked yetcites [1] Heidt T Courties G Dutta P Sager HB Sebas M Iwamoto Y Sun Y Da Silva N Panizzi P van der Laan AM Swirski FK Weissleder R Nahrendorf M Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res 2014 115 284 295 24786973 PMC4082439 source
A check is scheduled.
- Not checked yetcites [25] Epelman S Lavine KJ Beaudin AE Sojka DK Carrero JA Calderon B Brija T Gautier EL Ivanov S Satpathy AT Schilling JD Schwendener R Sergin I Razani B Forsberg EC Yokoyama WM Unanue ER Colonna M Randolph GJ Mann DL Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 2014 40 91 104 24439267 PMC3923301 source
A check is scheduled.
- Check pendingcites [26] Molawi K Wolf Y Kandalla PK Favret J Hagemeyer N Frenzel K Pinto AR Klapproth K Henri S Malissen B Rodewald HR Rosenthal NA Bajenoff M Prinz M Jung S Sieweke MH Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med 2014 211 2151 2158 25245760 PMC4203946 source
- Not checked yetcites [27] Lavine KJ Epelman S Uchida K Weber KJ Nichols CG Schilling JD Ornitz DM Randolph GJ Mann DL Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci U S A 2014 111 16029 16034 25349429 PMC4234568 source
A check is scheduled.
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Likewise, in atherosclerosis, the chronic lipid-driven inflammatory disease that is the underlying cause of MI, macrophage numbers increase in the vessel wall, again because of recruitment and local proliferation4.”
What the sources say
- Not checked yetcites [4] Robbins CS Hilgendorf I Weber GF Theurl I Iwamoto Y Figueiredo JL Gorbatov R Sukhova GK Gerhardt LM Smyth D Zavitz CC Shikatani EA Parsons M van Rooijen N Lin HY Husain M Libby P Nahrendorf M Weissleder R Swirski FK Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 2013 19 1166 1172 23933982 PMC3769444 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“We also know that macrophage function goes far beyond phagocytosis.”
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The heart and blood vessels of a healthy individual contain resident immune cells, the majority of which are macrophages that have seeded these organs early in development.”
What the sources say
- Not checked yetcites [1] Heidt T Courties G Dutta P Sager HB Sebas M Iwamoto Y Sun Y Da Silva N Panizzi P van der Laan AM Swirski FK Weissleder R Nahrendorf M Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res 2014 115 284 295 24786973 PMC4082439 source
- Not checked yetcites [2] Pinto AR Paolicelli R Salimova E Gospocic J Slonimsky E Bilbao-Cortes D Godwin JW Rosenthal NA An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLoS One 2012 7 e36814 22590615 PMC3349649 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Over the years, this paradigm was at times incorrectly fused with the concept of classical vs. alternative macrophage polarization, as proposed by Siamon Gordon in 199238.”
What the sources say
- Not checked yetcites [38] Stein M Keshav S Harris N Gordon S Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 1992 176 287 292 1613462 PMC2119288 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The problem with this perspective is that macrophages taken out of their native environments and placed in culture change dramatically: after a 7-day incubation period, cultured microglia and peritoneal macrophages completely lose their tissue-specific gene expression programs39.”
What the sources say
- Not checked yetcites [39] Gosselin D Link VM Romanoski CE Fonseca GJ Eichenfield DZ Spann NJ Stender JD Chun HB Garner H Geissmann F Glass CK Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 2014 159 1327 1340 25480297 PMC4364385 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In some cases, markers may break from the rule completely (i.e., more CCR2 expression in macrophages otherwise deemed M2).”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For one, identifying macrophage function according to a very specific stimulus, often given in vitro, does not attend to cell origins, tissue microenvironment, and time.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“We do have evidence for a stimulus-dependent activation macrophage network.”
What the sources say
- Not checked yetcites [40] Xue J Schmidt SV Sander J Draffehn A Krebs W Quester I De Nardo D Gohel TD Emde M Schmidleithner L Ganesan H Nino-Castro A Mallmann MR Labzin L Theis H Kraut M Beyer M Latz E Freeman TC Ulas T Schultze JL Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014 40 274 288 24530056 PMC3991396 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, a nomenclature based on stimulus is open-ended enough to become meaningless, because there are a nearly infinite combination of arbitrary stimuli, each yielding a “different” type of macrophage.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“What needs to be emphasized is that departure from the M1/M2 framework depends on the stimulus.”
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Indeed, if transplanted from one organ to another, macrophages adopt their new location's organ-specific transcriptional profiles35.”
What the sources say
- Not checked yetcites [35] Lavin Y Winter D Blecher-Gonen R David E Keren-Shaul H Merad M Jung S Amit I Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 2014 159 1312 1326 25480296 PMC4437213 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To conclude anything from these in vitro settings is to ignore the obvious: these are different cells.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A check of a cited source is scheduled, or we don’t hold its full text yet; the claim is checked once it runs.
In the paper
“but, in response to an inflammatory trigger, such as MI or high-fat diet, monocyte-derived cells accumulate and differentiate to self-renewing macrophages3, 4, 28, 29.”
What the sources say
- Check pendingcites [3] Hilgendorf I Gerhardt LM Tan TC Winter C Holderried TA Chousterman BG Iwamoto Y Liao R Zirlik A Scherer-Crosbie M Hedrick CC Libby P Nahrendorf M Weissleder R Swirski FK Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res 2014 114 1611 1622 24625784 PMC4017349 source
- Not checked yetcites [4] Robbins CS Hilgendorf I Weber GF Theurl I Iwamoto Y Figueiredo JL Gorbatov R Sukhova GK Gerhardt LM Smyth D Zavitz CC Shikatani EA Parsons M van Rooijen N Lin HY Husain M Libby P Nahrendorf M Weissleder R Swirski FK Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 2013 19 1166 1172 23933982 PMC3769444 source
A check is scheduled.
- Not checked yetcites [28] Nahrendorf M Swirski FK Aikawa E Stangenberg L Wurdinger T Figueiredo JL Libby P Weissleder R Pittet MJ The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007 204 3037 3047 18025128 PMC2118517 source
A check is scheduled.
- Check pendingcites [29] Swirski FK Libby P Aikawa E Alcaide P Luscinskas FW Weissleder R Pittet MJ Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007 117 195 205 17200719 PMC1716211 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In macrophage biology, we have little evidence for an all-encompassing spectrum.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
- Rests on an assumption: The M1/M2 paradigm is the prevailing model for understanding macrophage function.
In the paper
“Transcriptional profiling of human macrophages, for example, identified a broad transcriptional repertoire that challenges the M1/M2 paradigm.”
What the sources say
- Not checked yetcites [40] Xue J Schmidt SV Sander J Draffehn A Krebs W Quester I De Nardo D Gohel TD Emde M Schmidleithner L Ganesan H Nino-Castro A Mallmann MR Labzin L Theis H Kraut M Beyer M Latz E Freeman TC Ulas T Schultze JL Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014 40 274 288 24530056 PMC3991396 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“compelling evidence from GWAS studies have associated innate immunity mediators with myocardial infarction5”
What the sources say
- Not checked yetcites [5] Kathiresan S Voight BF Purcell S Musunuru K Ardissino D Mannucci PM Anand S Engert JC Samani NJ Schunkert H Erdmann J Reilly MP Rader DJ Morgan T Spertus JA Stoll M Girelli D McKeown PP Patterson CC Siscovick DS O'Donnell CJ Elosua R Peltonen L Salomaa V Schwartz SM Melander O Altshuler D Ardissino D Merlini PA Berzuini C Bernardinelli L Peyvandi F Tubaro M Celli P Ferrario M Fetiveau R Marziliano N Casari G Galli M Ribichini F Rossi M Bernardi F Zonzin P Piazza A Mannucci PM Schwartz SM Siscovick DS Yee J Friedlander Y Elosua R Marrugat J Lucas G Subirana I Sala J Ramos R Kathiresan S Meigs J source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 15
- It may state two separate claims as one. 9
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Forcing data onto the M1/M2 spectrum means opportunities for real discovery may be missed.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: Scientific models that are oversimplified and stifle discovery should be abandoned.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Just as T cells can be either cytotoxic or helpful – with at least three helper functions now identified – macrophages can be inflammatory, reparative, or something else.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Just as human activity extends well beyond a linear spectrum between standing still and sprinting, macrophage activity cannot be confined to a gradient of inflammatory intensity.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“Moreover, Mills explained, the two responses are T cell-independent, and their balance is regulated by TGFβ.”
What the sources say
- Not checked — no full text of the sourcecites [36] Mills CD Kincaid K Alt JM Heilman MJ Hill AM M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000 164 6166 6173 28923981 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the mouse, ~10% of non-cardiomyocytes are macrophages1, 2, and humans may have comparable numbers1.”
What the sources say
- Not checked yetcites [1] Heidt T Courties G Dutta P Sager HB Sebas M Iwamoto Y Sun Y Da Silva N Panizzi P van der Laan AM Swirski FK Weissleder R Nahrendorf M Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res 2014 115 284 295 24786973 PMC4082439 source
- Not checked yetcites [2] Pinto AR Paolicelli R Salimova E Gospocic J Slonimsky E Bilbao-Cortes D Godwin JW Rosenthal NA An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLoS One 2012 7 e36814 22590615 PMC3349649 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“After all, the word “macrophage” is itself a functional definition that has withstood the test of time.”
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Because they reside in nearly every organ, macrophages respond and adapt to their local surroundings, and their non-canonical activities reflect their flexibility.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Over time, the prevailing model was a macrophage spectrum, with M1 and M2 macrophages at the opposing ends and other groups of macrophages between.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: The M1/M2 paradigm is the prevailing model for understanding macrophage function.
None of the sources cited for this claim have been checked yet.
In the paper
“Introduced by Charlie Mills in 2000, the M1/M2 macrophage polarization paradigm36 was inspired by the Th1 vs. Th2 concept introduced four years earlier by Mosmann and Coffman37.”
What the sources say
- Not checked — no full text of the sourcecites [36] Mills CD Kincaid K Alt JM Heilman MJ Hill AM M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000 164 6166 6173 28923981 source
- Not checked yetcites [37] Mosmann TR Cherwinski H Bond MW Giedlin MA Coffman RL Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986 136 2348 2357 2419430
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“prospective human studies have shown that blood monocyte levels can predict cardiovascular events in patients6.”
What the sources say
- Not checked — no full text of the sourcecites [6] Berg KE Ljungcrantz I Andersson L Bryngelsson C Hedblad B Fredrikson GN Nilsson J Bjorkbacka H Elevated CD14++CD16- monocytes predict cardiovascular events. Circ Cardiovasc Genet 2012 5 122 131 22238190 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mills’ idea was built on the observation that LPS and IFNγ elicit divergent effects on macrophages isolated from different strains of mice. Whereas macrophages isolated from so-called Th1 strains (C57BL/6) produce nitric oxide (NO) in large quantities, the same triggers stimulate arginine metabolism to ornithine in macrophages isolated from Th2 strains (Balb/c).”
What the sources say
- Not checked — no full text of the sourcecites [36] Mills CD Kincaid K Alt JM Heilman MJ Hill AM M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000 164 6166 6173 28923981 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, such a nomenclature simply replaces one code for another and therefore requires a deciphering step in between.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Calling a macrophage “M(LPS)” is only marginally more informative than “M1” because one still has to dig to understand the function of an LPS-stimulated macrophage.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Beyond the reasons already mentioned, the reductive M1/M2 model arguably stifles rather than enables discovery.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: Scientific models that are oversimplified and stifle discovery should be abandoned.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In a science version of the game “telephone,” during which an original message shifts until it becomes unrecognizable, this “alternative” activation of less inflammatory macrophages became synonymous with “M2” macrophages.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“In vitro culture of human monocytes with M-CSF or GM-CSF, followed by activation with diverse stimuli, revealed considerable deviation from the M1/M2 axis, an insight that should be particularly relevant to investigators studying macrophage biology in cardiovascular disease because free fatty acids and high-density lipoprotein (HDL) molecules were among such stimuli40.”
What the sources say
- Not checked yetcites [40] Xue J Schmidt SV Sander J Draffehn A Krebs W Quester I De Nardo D Gohel TD Emde M Schmidleithner L Ganesan H Nino-Castro A Mallmann MR Labzin L Theis H Kraut M Beyer M Latz E Freeman TC Ulas T Schultze JL Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014 40 274 288 24530056 PMC3991396 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Over the years, this seemingly simple macrophage dichotomy has led to multiple cytokines and surface markers being sorted into one group or the other”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Murray and colleagues proposed naming macrophages according to the stimuli they encounter19.”
What the sources say
- Not checked yetcites [19] Murray PJ Allen JE Biswas SK Fisher EA Gilroy DW Goerdt S Gordon S Hamilton JA Ivashkiv LB Lawrence T Locati M Mantovani A Martinez FO Mege JL Mosser DM Natoli G Saeij JP Schultze JL Shirey KA Sica A Suttles J Udalova I van Ginderachter JA Vogel SN Wynn TA Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014 41 14 20 25035950 PMC4123412 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“From iron recycling in the spleen30, 31 and synaptic pruning in the brain32 to thermoregulation in brown fat33 and hematopoietic control in the bone marrow and spleen34, macrophages are remarkably adaptable.”
What the sources say
- Not checked yetcites [30] Haldar M Kohyama M So AY Kc W Wu X Briseno CG Satpathy AT Kretzer NM Arase H Rajasekaran NS Wang L Egawa T Igarashi K Baltimore D Murphy TL Murphy KM Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 2014 156 1223 1234 24630724 PMC4010949 source
- Not checked yetcites [31] Kohyama M Ise W Edelson BT Wilker PR Hildner K Mejia C Frazier WA Murphy TL Murphy KM Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 2009 457 318 321 19037245 PMC2756102 source
- Not checked yetcites [32] Hong S Beja-Glasser VF Nfonoyim BM Frouin A Li S Ramakrishnan S Merry KM Shi Q Rosenthal A Barres BA Lemere CA Selkoe DJ Stevens B Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016 352 712 716 27033548 PMC5094372 source
- Not checked yetcites [33] Nguyen KD Qiu Y Cui X Goh YP Mwangi J David T Mukundan L Brombacher F Locksley RM Chawla A Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 2011 480 104 108 22101429 PMC3371761 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The M1/M2 paradigm is the prevailing model for understanding macrophage function.
“A handy and consequently persistent shorthand for understanding macrophage function groups the cells into either M1 or M2 responses.”
“Over time, the prevailing model was a macrophage spectrum, with M1 and M2 macrophages at the opposing ends and other groups of macrophages between.”
The paper relies on this without support.
Scientific models that are oversimplified and stifle discovery should be abandoned.
“Should we abandon the M1/M2 paradigm altogether? Beyond the reasons already mentioned, the reductive M1/M2 model arguably stifles rather than enables discovery.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Although macrophages have traditionally been classified as either classically-activated (M1) or alternatively-activated (M2), it is now recognised that they exist along a continuum of activation states 8 , with M1 and M2 representing the prototypical pro-and anti-inflammatory extremes of this spectrum 9 .”
From Soft tissue-mimicking hydrogel stiffness modulates polarisation of human monocyte-derived macrophages (2025) · cites this paper as [9]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Abandoning M1/M2 for a Network Model of Macrophage Function
“Introduced by Charlie Mills in 2000, the M1/M2 macrophage polarization paradigm36 was inspired by the Th1 vs. Th2 concept introduced four years earlier by Mosmann and Coffman37.”
§ Abandoning M1/M2 for a Network Model of Macrophage Function > References
“37. Mosmann TR Cherwinski H Bond MW Giedlin MA Coffman RL Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986 136 2348 2357 2419430”
Citations
Cites
Mosmann, T. R., Cherwinski, H. M., Bond, M. W., Giedlin, M. A., & Coffman, R. L. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.136.7.2348 · Cited by 7,559
Macrophage activation and polarization: nomenclature and experimental guidelines
Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W., Goerdt, S., Gordon, S., Hamilton, J. A., Ivashkiv, L. B., Lawrence, T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.008 · Cited by 6,337
Macrophage biology in development, homeostasis and disease
Wynn, T. A., Chawla, A., & Pollard, J. W. (2013) · Nature · doi:10.1038/nature12034 · Cited by 4,684
Macrophages in Tissue Repair, Regeneration, and Fibrosis
Wynn, T. A., & Vannella, K. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.015 · Cited by 4,481
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343
M-1/M-2 Macrophages and the Th1/Th2 Paradigm
Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., & Hill, A. M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.12.6166 · Cited by 3,287
Development of Monocytes, Macrophages, and Dendritic Cells
Geissmann, F., Manz, M. G., Jung, S., Sieweke, M. H., Merad, M., & Ley, K. (2010) · Science · doi:10.1126/science.1178331 · Cited by 3,049
Nahrendorf, M., Swirski, F. K., Aikawa, E., Stangenberg, L., Wurdinger, T., Figueiredo, J.-L., Libby, P., Weissleder, R., & Pittet, M. J. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070885 · Cited by 2,300
Self-citationTranscriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation
Xue, J., Schmidt, S. V., Sander, J., Draffehn, A., Krebs, W., Quester, I., De Nardo, D., Gohel, T. D., Emde, M., Schmidleithner, L., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.01.006 · Cited by 2,210
Cited by
Sorted by citations
Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span
Misharin, A. V., Morales-Nebreda, L., Reyfman, P. A., Cuda, C. M., Walter, J. M., McQuattie-Pimentel, A. C., Chen, C.-I., Anekalla, K. R., Joshi, N., Williams, K. J. N., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162152 · Cited by 1,133
Falanga, V., Isseroff, R. R., Soulika, A. M., Romanelli, M., Margolis, D. J., Kapp, S., Granick, M. S., & Harding, K. G. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00377-3 · Cited by 1,160
The role of macrophages in the resolution of inflammation
Watanabe, S., Alexander, M., Misharin, A. V., & Budinger, G. R. S. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124615 · Cited by 925
Cochain, C., Vafadarnejad, E., Arampatzi, P., Pelisek, J., Winkels, H., Ley, K., Wolf, D., Saliba, A.-E., & Zernecke, A. (2018) · Circulation Research · doi:10.1161/circresaha.117.312509 · Cited by 894
Bajpai, G., Bredemeyer, A., Li, W., Zaitsev, K., Koenig, A. L., Lokshina, I., Mohan, J., Ivey, B., Hsiao, H.-M., Weinheimer, C., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314028 · Cited by 751
Metadata
- Authors
- Nahrendorf, M., & Swirski, F. K.
- Affiliations
- Harvard University (US)
- From the Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston.
- ORCID
- Nahrendorf, Matthias
- Venue
- Circulation Research
- Published
- 2016-07-22
- Volume
- 119
- Issue
- 3
- Pages
- 414-417
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4965179
- OpenAlex
- W2505661818
- Cited by
- 525
- References
- 41
- Citations by year
- 2026: 59 · 2025: 63 · 2024: 54 · 2023: 74 · 2022: 60 · 2021: 75 · 2020: 53 · 2019: 35 · 2018: 35 · 2017: 16 · 2016: 1
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HL128264)
- National Heart, Lung, and Blood Institute (R01HL117829, R01HL095629, R01HL128264, R01HL096576, R01HL095612)
- National Institute of Neurological Disorders and Stroke (R01NS084863)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- macrophage polarization, M1/M2 macrophages, network models, macrophage function, macrophage heterogeneity
- MeSH terms
- Animals, Humans, Macrophages, Models, Biological, Myocardial Infarction, Macrophage-1 Antigen, Galectin 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
