Impact of JAK/STAT inhibitors on human monocyte‐derived‐macrophages stimulated by cigarette smoke extract and lipopolysaccharide

Abstract

The main risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoke (CS). It can alter many immune cells functions such as phagocytosis, efferocytosis and cytokine production. Cytokines play a role in the orchestration of inflammation in COPD. The JAK/STAT pathways are among the most important signalling components of cytokines. The objective of this work was to investigate the role of the JAK/STAT pathway with regard to cytokine release and microsphere uptake capacity (to minimize the non-specific scavenging) in human monocyte-derivedmacrophages (MDMs). The MDMs were stimulated by cigarette smoke extract (CSE) alone or in combination with lipopolysaccharide (LPS). CSE alone was not associated with significant changes in the cytokine, with the exception of IL-8/CXCL8 production. However, CSE disturbed cytokine production in LPS-stimulated MDMs. CSE increase CXCL-8 and CCL2 release in LPS-stimulated monocyte-derived macrophages and suppressed the production of IL-6 and CXCL1 in these cells. CSE also decreased microsphere uptake capacity by MDMs. Then, CSE + LPS-stimulated MDMs were treated with two different JAK inhibitors. AG490 (specific inhibitor of JAK2) and ruxolitinib (inhibitor of JAK1 and JAK2). JAK/STAT inhibitors, particularly ruxolitinib, attenuated in cytokine production without completely inhibiting when compared with dexamethasone. On the other hand, the cells exposed to dexamethasone are nearly unable to capture the microspheres, while both JAK inhibitors do not affect the uptake capacity. In summary, our results showed the versatility of ruxolitinib which might bring a better balance disturbance of cytokine release and uptake capacity. The information regarding the distinctive effect of JAK/STAT inhibitors may be useful in the development of novel treatments for COPD.

Macrophages exploit the mannose receptor and JAK-STAT1-MHC-II pathway to drive antigen presentation and the antimycobacterial immune response to BCG vaccination

“…Because the JAK/STAT pathway, a rapid membrane-to-nucleus signaling pathway, induces the expressions of various critical mediators during infection and is essential for the immunomodulation of innate and adaptive immunity [15,16], we investigated this pathway in both WT and Mr -/-BMDMs upon BCG stimulation. BMDMs from Mr -/and WT mice were incubated with BCG for 0.5, 1 or 3 h, and the phosphorylation of JAK1 and STAT1 was determined by immunoblotting analysis (Figure 5A).…”