Vitamin D protects silica particles induced lung injury by promoting macrophage polarization in a KLF4-STAT6 manner

ElsevierVolume 110, December 2022, 109148The Journal of Nutritional BiochemistryAbstract

Silicosis is one of the severest occupational diseases worldwide, manifesting as infiltration of inflammatory cells, excessive secretion of pro-inflammatory mediators and pulmonary diffuse fibrosis. Macrophages polarization to M2 is one of the major strategies that attenuates inflammatory response. Our previous study found that vitamin D could protect against silica-induced lung injury by damping the secretion of pro-inflammatory cytokines. Here we further identified that vitamin D attenuated silica particles-induced lung inflammation by regulating macrophage polarization in a KLF4-STAT6 manner. Myeloid-specific Stat6 knockout (cKO) mice were generated for in vivo studies. Primary macrophages purified from bronchoalveolar lavage fluid (BALF) of wildtype or Stat6 cKO mice and differentiated THP-1 cells were used for in vitro studies. Vitamin D was found to promote alveolar macrophage polarizing to M2 phenotype through the STAT6 signaling pathway, as demonstrated by worse lung inflammation and ablated protection of vitamin D in silica particles-instilled Stat6 cKO mice. Mechanismly, vitamin D upregulated KLF4 expression in the alveolar macrophage, which synergistically activated STAT6. Additionally, KLF4 was found to upregulate macrophages autophagy, which protected them from silica particles-induced oxidative stress and cell apoptosis. The protective effects of vitamin D were dismissed by silencing KLF4. Our study demonstrates the potential mechanism of vitamin D-mediated macrophage polarization and reveals the therapeutic application of vitamin D in inflammatory disease.

Graphical Abstract

Image, graphical abstractDownload : Download high-res image (104KB)Download : Download full-size imageVitamin D ameliorates silica particles-induced pulmonary injury by inhibiting related inflammatory cytokines and promoting macrophage polarizing to anti-inflammatory M2 phenotype based on STAT6 signaling pathway. Mechanismly, vitamin D induces the expression of KLF4, which synergistically activates STAT6 and promotes its nucleus translocation and then transcripts downstream genes, which promote macrophages polarizing to M2. In addition, vitamin D also up-regulates autophagy in macrophages against cell apoptosis through KLF4.

Key words

Vitamin D

Silica particles

Macrophage polarization

Pulmonary inflammatory injury

STAT6

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