Rab32‐related antimicrobial pathway is involved in the progression of dextran sodium sulfate‐induced colitis

Abstract

Inflammatory bowel disease ( IBD ) is a multifactorial disease involving defective immune responses against invasive microbiota. Genes associated with innate immune responses to microbes have been highlighted in the pathogenesis of IBD . To determine the role of Rab32 in the pathogenesis of IBD , we administered dextran sodium sulfate ( DSS ) to CD 11c + cell‐specific Rab32 knockout ( CD 11c ‐Cre + Rab32 f/f ) mice to induce colitis. Rab32 deficiency in CD 11c + cells resulted in more severe disease progression and increased mortality. Histopathological analysis showed extensive damage to the colon mucosa in DSS ‐treated CD 11c ‐Cre + Rab32 f/f mice, including more severe damage to the epithelial layer and crypts, as well as more inflammatory cell infiltration. The pro‐inflammatory cytokines IL 1A, IL 1B, IL 6, and CSF 3 and chemokines CXCL 1 and CXCL 2 were significantly increased, and the frequency of CD 11b + Ly6G + neutrophils was higher in CD 11c ‐Cre + Rab32 f/f colitis mice. Furthermore, CD 11c + cells deficient for Rab32 exhibited a significant increase in bacterial translocation in inflamed colon tissue. The present data demonstrate that Rab32 knockout in CD 11c + cells aggravates the development of DSS ‐induced colitis and suggest that the Rab32‐related antimicrobial pathway is involved in the pathogenesis of IBD .

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

“…Alternatively or additionally, since heritable forms of inflammatory bowel syndrome are often associated with innate immune defects, the impact of BLOC‐3 and RAB32 in macrophages and monocytes might underlie the susceptibility. Consistent with the latter, conditional knockout of Rab32 in CD11c + cells (dendritic cells, monocytes and other innate immune cells) causes increased susceptibility to dextran sodium sulfate‐induced colitis and enhanced production of proinflammatory cytokines and chemokines . It will be important to validate this finding in the human system and to determine if the inflammatory response underlies the susceptibility to colitis in HPS1 and 4 patients.…”

Weight loss is a sufficient and economical single outcome measure of murine dextran sulfate sodium colitis

“…For instance, some used weight loss, stool consistency, and visual blood in the stool . Other variations included weight loss, stool consistency and visual rectal bleeding or weight loss, stool consistency, general appearance, and visual rectal bleeding . Therefore, the only objectively measured component within these DAIs was weight loss.…”

“…27,33 Other variations included weight loss, stool consistency and visual rectal bleeding 34 or weight loss, stool consistency, general appearance, and visual rectal bleeding. 35 Therefore, the only objectively measured component within these DAIs was weight loss. Based on discussions with colleagues in the field, DAI measurements are not blinded, hence the remaining factors assessed beyond weight loss are subjective and prone to bias.…”

A pathogenic variant in RAB32 causes autosomal dominant Parkinson’s disease andactivates LRRK2 kinase

“…Upon infection, RAB32 interacts with the mitochondrial immunoresponsive gene 1 (IRG1) product aconitate decarboxylase 1 (ACOD1) and facilitates the delivery of itaconic acid to the pathogen-containing vacuole to inhibit bacterial growth 27 . While germline RAB32 knockout is lethal, in dendritic cells it results in increased pathogen load in liver and spleen after bacterial infection, and knockout increases susceptibility to, and morbidity and mortality of, DSS-induced colitis 28 . RAB32 also supports the mechanistic target of rapamycin complex I (mTORC1) signaling under basal and amino-acid stimulated conditions 29 , and is reported to control sorting to lysosome-related organelles 30 including melanosome biosynthesis/recycling in melanocytes 30 .…”