Toll-like Receptor 2 Prevents Neutrophil-Driven Immunopathology during Infection with Mycobacterium tuberculosis by Curtailing CXCL5 Production

Abstract

The W-Beijing strain family is globally distributed and is associated with multidrug-resistant tuberculosis (TB) and treatment failure. Therefore, in this study, we examined the contribution of Toll-like receptor 2 (TLR2) to host resistance against Mycobacterium tuberculosis HN878, a clinical isolate belonging to the W-Beijing family. We show that TLR2 knockout (TLR2KO) mice infected with M. tuberculosis HN878 exhibit increased bacterial burden and are unable to control tissue-damaging, pulmonary neutrophilic inflammation. Consistent with a critical role for CXCL5 in regulating neutrophil influx, expression of epithelial cell-derived CXCL5 is significantly enhanced in TLR2KO mice prior to their divergence from wild-type (WT) mice in M. tuberculosis replication and neutrophilic inflammation. Depletion of neutrophils in TLR2KO mice by targeting Ly6G reverts lung inflammation and bacterial burden to levels comparable to those of WT mice. Together, the results establish that TLR2 controls neutrophil-driven immunopathology during infection with M. tuberculosis HN878 infection, likely by curtailing CXCL5 production.

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

“…In the lung of Ppara -/mice, Cxcl5 and Cxcl10 expression levels were significantly increased. The chemokine CXCL5 is involved in the regulation of neutrophil influx and pulmonary neutrophil inflammation during M. tuberculosis infection [46][47][48]. In addition, the Cxcl5 mRNA level was significantly increased in macrophages and epithelial cells in Sirt3-deficient lung during M. tuberculosis infection [47].…”

“…In addition, the Cxcl5 mRNA level was significantly increased in macrophages and epithelial cells in Sirt3-deficient lung during M. tuberculosis infection [47]. Neutrophil depletion by targeting Ly6G reportedly enhances host defense against M. tuberculosis infection in mice [46][47][48]. In addition, whether CXCL10 is increased in Mabc patients or Mabc infection models is unclear.…”

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

“…Similar results were obtained when Gr-1 and CD18 levels were measured on S100A9KO Mtb-infected neutrophils when compared with B6 Mtb-infected neutrophils ( Figure 6B). This coincided with increased induction of mRNA for signaling receptors, such as TLR2 and TLR4, and phagocytic receptors, such as C-type lectin receptor and macrophage inducible Ca 2+ -dependent lectin receptor (MINCLE), which play a role in phagocytosis of Mtb (23,24), but not formyl peptide receptor 1 (FPR1) or DECTIN-1 (Figure 6C). This increased expression of phagocytic receptors on Table 2.…”

Latest Comprehensive Knowledge of the Crosstalk between TLR Signaling and Mycobacteria and the Antigens Driving the Process

“…In TLR2 KO mice, Mtb increases the bacterial burden and disturbs the control of neutrophilic inflammation. TLR2 downregulates CXCL5 production to prevent neutrophil-mediated pathology during Mtb infection [43]. In addition, TLR2 cooperates with other TLR family including TLR4 [44] and TLR9 during Mtb infection.…”

“…Induction of pro-inflammatory cytokines Mtb [35][36][37] Induction of ROS generation, chemokine production, and MAPK activation Mtb [38,39] Reduction of bacterial burden Mtb [40][41][42] Reduction of neutrophil-derived inflammation by regulating CXCL5 production Mtb [43] TLR3 Induction of IL-10 via the PI3K/AKT signaling pathway BCG [46] Progression of infection through activation of TLR3 pathway using poly (I:C) Mtb [47,48] TLR4 Induction of phagocytosis Mtb [53] Induction of pro-inflammatory cytokine Mtb, BCG [54,55,61] Control of the balance cell death Mtb [63] TLR7 Induction of killing bacteria through autophagy Mtb [64] TLR9 Induction of pro-inflammatory cytokines Mtb [37] Induction of Th1 response and Th1-associated cytokine IFN-γ Mtb [72] through poly (I:C)-encapsulating nanoparticles enhances the pro-inflammatory immune response to BCG-infected macrophages in a synergistic manner [49]. A novel liposome adjuvant, dimethyl dioctadecyl ammonium bromide combined with poly (I:C) and cholesterol (DPC), can play a role in Mtb subunit vaccine development.…”