Cigarette Smoke Induces Intestinal Inflammation via a Th17 Cell-Neutrophil Axis

Abstract

Epidemiological evidence finds cigarette smoking is a common risk factor for a number of diseases, not only in the lung but also in other tissues, such as the gastrointestinal tract. While it is well-documented that smoking directly drives lung inflammatory disease, how it promotes disease in peripheral tissues is incompletely understood. In this study, we utilized a mouse model of short-term smoke exposure and found increased Th17 cells and neutrophilia in the lung as well as in the circulation. Following intestinal inflammatory challenge, smoke exposed mice showed increased pathology which corresponds to enhanced intestinal Th17 cells, ILC3 and neutrophils within intestinal tissue. Using cellular depletion and genetic deficiencies, we define a cellular loop by which IL-17A and downstream neutrophils drive cigarette smoke-enhanced intestinal inflammation. Collectively, cigarette smoke induced local lung Th17 responses lead to increased systemic susceptibility to inflammatory insult through enhanced circulating neutrophils. These data demonstrate a cellular pathway by which inflammatory challenge in the lung can sensitize the intestine to enhanced pathological innate and adaptive immune responses.

Effects of sex and chronic cigarette smoke exposure on the mouse cecal microbiome

“…Apart from the neurophysiological effects of smoking, which is associated with decreased appetite and changes in plasma leptin levels [53], smoking also interferes negatively with the gut homeostasis by promoting increased mucosal inflammation and decreased intestinal mucosal barrier integrity. In a previous study, mice exposed to two months of smoke exposure followed by a 6-day treatment with dextran sodium sulfate (DSS) (induced-colitis model) showed enhanced gut inflammation via increased neutrophil counts and Th17+ cells in the lungs, blood and intestinal compartments, supporting the existence of a lung-gut axis [54]. Those findings are in keeping with reports from Allais and colleagues, who observed altered mucin production and increased expression of inflammatory genes (Cxcl2 and IL-6) in the murine gut following chronic smoke exposure, and those changes were accompanied by an increase in the relative abundance of Lachnospiraceae sp.…”

Links Between Inflammatory Bowel Disease and Chronic Obstructive Pulmonary Disease

“…A promoter variant in the gene encoding the aryl hydrocarbon receptor (AHR) has been linked to increased risk of intestinal hyperpermeability, with cigarette smoking further increasing this risk ( 109 ). From an immunological perspective, cigarette smoke induces an IL-17 response with increases in Th17 cells and neutrophils in the lungs and circulation ( 110 ). This enhances intestinal Th17 cells and neutrophils, as well as IL-17-producing type 3 innate lymphoid cells (ILC3s), in a manner that is dependent on neutrophil recruitment via IL-17A ( 110 ).…”

Defective intestinal repair after short-term high fat diet due to loss of efferocytosis

“…During intestinal damage monocyte-derived macrophages and neutrophils are recruited to sites of injury and their numbers decrease after resolution of damage. Increased presence of inflammatory macrophages, monocytes and neutrophils in intestinal tissue supports inflammation 20,21 . We used immunofluorescence staining and flow cytometric analysis to assess monocyte, macrophage and neutrophil recruitment in LFD and HFD mice after intestinal injury.…”

“…Increased neutrophil numbers and inefficient clearance of apoptotic neutrophils can result in impaired tissue resolution 21,22 . To investigate whether accumulation of neutrophils was required for increased pathology after HFD, we depleted neutrophils in HFD mice after the start of DSS treatment.…”