Toll-like Receptor 4 Is a Sensor for Autophagy Associated with Innate Immunity
Open accessAbstract
Autophagy has recently been shown to be an important component of the innate immune response. The signaling pathways leading to activation of autophagy in innate immunity are not known. Here we showed that Toll-like receptor 4 (TLR4) served as a previously unrecognized environmental sensor for autophagy. Autophagy was induced by lipopolysaccharide (LPS) in primary human macrophages and in the murine macrophage RAW264.7 cell line. We defined a new molecular pathway in which LPS-induced autophagy was regulated through a Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-dependent, myeloid differentiation factor 88 (MyD88)-independent TLR4 signaling pathway. Receptor-interacting protein (RIP1) and p38 mitogen-activated protein kinase were downstream components of this pathway. This signaling pathway did not affect cell viability, indicating that it is distinct from the autophagic death signaling pathway. We further showed that LPS-induced autophagy could enhance mycobacterial colocalization with the autophagosomes. This study links two ancient processes, autophagy and innate immunity, together through a shared signaling pathway.
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Invading pathogens are recognized by mammalian cells through receptors found either at the cell surface (e.g., TLRs) or in the cytoplasm (NLRs).
“Invading pathogens are recognized by mammalian cells through receptors found either at the cell surface (eg, trans-membrane Toll-like Receptors; TLRs), or in the cytoplasm (Nod-like Receptors (NLRs) [36,37].”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [37]
The Introduction states that TLRs detect microbes, and the Results show that TLR4 mediates a response to bacterial LPS. Our copy does not establish the claimed cell-surface location of TLRs or discuss cytoplasmic NLRs, so it supports only the TLR recognition part of the sentence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTLR4-NF-κB signaling induces selective autophagy after pathogen invasion.
“TLR4-NF-κB signaling was previously shown to induce selective autophagy after pathogen invasion52–54.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [54]
The Results show that LPS induces autophagy through TLR4, and the Discussion identifies a TRIF-dependent pathway involving RIP1 and p38 MAPK. The paper also reports colocalization of mycobacterial phagosomes with autophagosomes, but it does not establish NF-κB as the mediator or characterize the response as selective autophagy after pathogen invasion. (LLM, conf=0.88)
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“Furthermore, LPS upregulated LRG47, a GTPase that has been recently shown to be involved in antimycobacterial effects through contribution to autophagy induction (MacMicking et al., 2003; Gutierrez et al., 2004).”
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- Authors
- Xu, Y., Jagannath, C., Liu, X.-D., Sharafkhaneh, A., Kolodziejska, K. E., & Eissa, N. T.
- Affiliations
- Baylor College of Medicine (US)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Eissa, N. Tony
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 27
- Issue
- 1
- Pages
- 135-144
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2680670
- OpenAlex
- W1988327539
- Cited by
- 880
- References
- 4
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 24 · 2023: 25 · 2022: 44 · 2021: 48 · 2020: 48 · 2019: 38 · 2018: 49 · 2017: 54 · 2016: 56 · 2015: 40 · 2014: 62 · 2013: 85 · 2012: 71
- FWCI
- 17.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2208 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Historical Association
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health (1F32 HL078520-01)
- Alpha-1 Foundation
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Keywords
- TLR4, autophagy, innate immunity, lipopolysaccharide, macrophages, TRIF, MyD88-independent signaling, RIPK1, p38 MAPK, autophagosomes, mycobacteria, autophagy signaling
- MeSH terms
- Animals, Autophagy, Cell Line, Humans, Immunity, Innate, Lipopolysaccharides, Macrophages, Mycobacterium tuberculosis, Signal Transduction, Toll-Like Receptor 4, Mice
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