Lipopolysaccharide (LPS), commonly known as endotoxin, is ubiquitous and the most-studied pathogen-associated molecular pattern. A component of Gram-negative bacteria, extracellular LPS is sensed by our immune system via the toll-like receptor (TLR)-4. Given that TLR4 is membrane bound, it recognizes LPS in the extracellular milieu or within endosomes. Whether additional sensors, if any, play a role in LPS recognition within the cytoplasm remained unknown until recently. The last decade has seen an unprecedented unfolding of TLR4-independent LPS sensing pathways. First, transient receptor potential (TRP) channels have been identified as non-TLR membrane-bound sensors of LPS and, second, caspase-4/5 (and caspase-11 in mice) have been established as the cytoplasmic sensors for LPS. Here in this review, we detail the brief history of LPS discovery, followed by the discovery of TLR4, TRP as the membrane-bound sensor, and our current understanding of caspase-4/5/11 as cytoplasmic sensors.
Leishmania spp. infection is a global health problem affecting more than 2 million people every year with 300 million at risk worldwide. It is well established that a dominant Th1 response (IFN-γ, a hallmark Th1 cytokine) provides resistance, whereas a dominant Th2 response (IL-4, a hallmark Th2 cytokine) confers susceptibility during infection. Given the important role of IL-4 during L. major infection, we used IL-4–neutralizing Abs to investigate the cellular and molecular events regulated by IL-4 signaling. As previously published, neutralization of IL-4 in L. major –infected BALB/c mice (a Leishmania susceptible strain) provided protection when compared with control L. major –infected BALB/c mice. Despite this protection, IFN-γ production by T cells was dramatically reduced. Temporal neutralization of IL-4 revealed that acute IL-4 produced within the first days of infection is critical for not only programming IL-4–producing Th2 CD4 + T cells, but for promoting IFN-γ produced by CD8 + T cells. Mechanistically, IL-4 signaling enhances anti-CD3–induced Tbet and IFN-γ expression in both CD4 + and CD8 + T cells. Given the pathogenic role of IFN-γ–producing CD8 + T cells, our data suggest that IL-4 promotes cutaneous leishmaniasis pathology by not only promoting Th2 immune responses but also pathogenic CD8 + T cell responses. Our studies open new research grounds to investigate the unsuspected role of IL-4 in regulating both Th1 and Th2 responses. ImmunoHorizons , 2020, 4: 546–560.
Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year and more than 1 billion people at risk of contracting this disease in endemic areas. The innate immune system plays a central role in controlling L . major infection by initiating a signaling cascade that results in production of pro-inflammatory cytokines and recruitment of both innate and adaptive immune cells. Upon infection with L . major , CXCL1 is produced locally and plays an important role in the recruitment of neutrophils to the site of infection. Herein, we report that L . major specifically targets murine CXCL1 for degradation. The degradation of CXCL1 is not dependent on host factors as L . major can directly degrade recombinant CXCL1 in a cell-free system. Using mass spectrometry, we discovered that the L . major protease cleaves at the C-terminal end of murine CXCL1. Finally, our data suggest that L . major metalloproteases are involved in the direct cleavage and degradation of CXCL1, and a synthetic peptide spanning the CXCL1 cleavage site can be used to inhibit L . major metalloprotease activity. In conclusion, our study has identified an immune evasion strategy employed by L . major to evade innate immune responses in mice, likely reservoirs in the endemic areas, and further highlights that targeting these L . major metalloproteases may be important in controlling infection within the reservoir population and transmittance of the disease.
Mice with SHP1 proteins, which have a single amino acid substitution from tyrosine-208 residue to asparagine (hereafter Ptpn6 spin mice), develop an autoinflammatory disease with inflamed footpads. Genetic crosses to study CD47 function in Ptpn6 spin mice bred Ptpn6 spin × Cd47 −/− mice that were not born at the expected Mendelian ratio. Ptpn6 spin bone marrow cells, when transferred into lethally irradiated Cd47 -deficient mice, caused marked weight loss and subsequent death. At a cellular level, Ptpn6 -deficient neutrophils promoted weight loss and death of the lethally irradiated Cd47 −/− recipients. We posited that leakage of gut microbiota promotes morbidity and mortality in Cd47 −/− mice receiving Ptpn6 spin cells. Colonic cell death and gut leakage were substantially increased in the diseased Cd47 −/− mice. Last, IL-1 blockade using anakinra rescued the morbidity and mortality observed in the diseased Cd47 −/− mice. These data together demonstrate a protective role for CD47 in tempering pathogenic neutrophils in the Ptpn6 spin mice.
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