TLR-induced activation of Btk – Role for endosomal MHC class II molecules revealed

Gabhann, Joan Ní; Jefferies, Caroline A.

doi:10.1038/cr.2011.88

Cited by 12 publications

(12 citation statements)

References 12 publications

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“…Moreover, MHCII seems to play a functional role, as MHCII‐deficient animals reportedly display impaired de‐ and remyelination . Finally, the defect also persisted in I‐Aβ −/− animals reconstituted with truncated I‐A b molecules (I‐Aβtr) lacking cytoplasmic domains, leading to the conclusion, that MHCII might exert signaling activity, as also suggested by others . Specifically, I‐A b−/− and I‐A b−/− : I‐Aβtr mice displayed fewer proliferating microglia/macrophages and reduced amounts of brain TNFα, IL‐1β, and nitric oxide compared to WT mice, suggesting a role for MHCII in microglia activation .…”

Section: Introductionsupporting

confidence: 53%

Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone‐induced demyelination

et al. 2018

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Microglia are resident immune cells in the CNS, strategically positioned to clear dead cells and debris, and orchestrate CNS inflammation and immune defense. In steady state, these macrophages lack MHC class II (MHCII) expression, but microglia activation can be associated with MHCII induction. Whether microglial MHCII serves antigen presentation for critical local T-cell restimulation in CNS auto-immune disorders or modulates microglial signaling output remains under debate. To probe for such scenarios, we generated mice harboring an MHCII deficiency in microglia, but not peripheral myeloid cells. Using the CX CR1 -based approach we report that microglial antigen presentation is obsolete for the establishment of EAE, with disease onset, progression, and severity unaltered in mutant mice. Antigen presentation-independent roles of microglial MHCII were explored using a demyelination model induced by the copper chelator cuprizone. Absence of microglial I-A did not affect the extent of these chemically induced white matter alterations, nor did it affect microglial proliferation or gene expression associated with locally restricted de- and remyelination.

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Section: Introductionsupporting

confidence: 53%

Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone‐induced demyelination

et al. 2018

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“…Consequently, decreased expression of these particular cytokines is likely to be mediated through preventing BTK-mediated macrophage polarization. Furthermore, BTK may also be important for downstream signaling of TLRs, specifically downstream of TLR4-dependent expression of IL-10 [ 14 , 28 ]. The relevance of the latter mechanism here is supported by the decrease we found in skin IL-10 levels in BTK-I-treated mice.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, BTK is vital for B cell development, survival, and function (e.g. B cell receptor (BCR) and toll-like receptor (TLR) signaling), while in macrophages BTK mediates Fc receptor and TLR signaling and macrophage polarization [ 11 – 14 ]. These pivotal roles for BTK in both B cells and macrophages indicate that this enzyme could potentially be a valuable therapeutic target in different end-organ pathologies in SLE.…”

Section: Introductionmentioning

confidence: 99%

Highly selective inhibition of Bruton’s tyrosine kinase attenuates skin and brain disease in murine lupus

et al. 2018

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BackgroundSystemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE.MethodsWe used a novel inhibitor of Bruton’s tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease.ResultsWe found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus.ConclusionsDirected therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1500-0) contains supplementary material, which is available to authorized users.

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“…To understand further the mechanism by which the activation of TLR signaling in macrophages promoted tumor cell phagocytosis, we treated macrophages by combining TLR agonists with various inhibitors targeting key molecules that positively (MAPK, Btk) (23)(24)(25)(26)(27) or negatively (PI3K, caspase-1) (28,29) regulate TLR signaling. Blockers of MAPK, PI3K, and caspase-1 showed no effect on phagocytosis of cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk

Feng

Chen

Weissman-Tsukamoto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

229

199

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Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don’t-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages. Here we demonstrate that the activation of Toll-like receptor (TLR) signaling pathways in macrophages synergizes with blocking CD47 on tumor cells to enhance PrCR. Bruton’s tyrosine kinase (Btk) mediates TLR signaling in macrophages. Calreticulin, previously shown to be an eat-me signal on cancer cells, is activated in macrophages for secretion and cell-surface exposure by TLR and Btk to target cancer cells for phagocytosis, even if the cancer cells themselves do not express calreticulin.

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TLR-induced activation of Btk – Role for endosomal MHC class II molecules revealed

Cited by 12 publications

References 12 publications

Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone‐induced demyelination

Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone‐induced demyelination

Highly selective inhibition of Bruton’s tyrosine kinase attenuates skin and brain disease in murine lupus

Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk

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