Toll-like receptor 2 coordinates induction of IL-22 in lung macrophages following organic dust-induced inflammation

IntroductionOrganic dust exposures, particularly in occupational settings, induce airway inflammation and contribute to the development and progression of chronic lung disease and impaired tissue regeneration. Interleukin-22 (IL-22) is a pleiotropic cytokine recognized for maintaining epithelial barrier integrity and promoting tissue repair; however, its regulation in lung myeloid cells, particularly macrophages, remains poorly understood. Toll-like receptor 2 (TLR2), a pattern recognition receptor highly expressed on lung macrophages, recognizes bacterial components abundant in organic dust and drives inflammatory signaling. We investigated the mechanistic role of TLR2 signaling in regulating IL-22 production by lung macrophages following exposure to microbial-enriched agricultural organic dust extract (DE).MethodsAn immortalized lung macrophage cell line (MH-S) was stimulated with selective Toll-like receptor agonists and pharmacologic inhibitors to determine the contribution of individual TLR pathways to IL-22 production. To examine the role of TLR2 in vivo, wild-type (WT) and TLR2-deficient (tlr2-/-) mice were exposed to DE repeatedly for two weeks. IL-22 expression and macrophage localization were evaluated using RNAscope in situ hybridization and immunofluorescence analysis.ResultsTLR2 stimulation preferentially induced IL-22 production compared with other TLR pathways while simultaneously coordinating pro-inflammatory cytokine responses. Activation of the TLR2/1 heterodimer, but not TLR2/6, significantly increased IL-22 production, indicating pathway-specific regulation of reparative signaling. In vivo, repeated DE exposure resulted in significantly reduced pulmonary IL-22 expression in tlr2-/- mice compared with WT controls. Furthermore, tlr2-/- lungs exhibited fewer IL-22+CD68+ cells, an overall reduction in macrophage numbers, and a significant decrease in the proportion of CD68+ macrophages expressing IL-22, suggesting that TLR2 is required for both macrophage accumulation and IL-22 production during dust-induced lung injury. Discussion/ConclusionThese findings identify TLR2 as a critical regulator of IL-22-mediated reparative programming in lung macrophages following organic dust exposure. Our study reveals a previously unrecognized link between innate immune sensing and epithelial repair pathways, providing mechanistic insight into how TLR2 promotes tissue restoration after environmental lung injury. Targeting the TLR2-IL-22 axis may represent a promising therapeutic strategy for mitigating occupational dust-induced lung damage.