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Abstract
The human host defense peptide LL-37 promotes immune activation such as induction of chemokine production and recruitment of leukocytes. Conversely, LL-37 also mediates anti-inflammatory responses such as production of anti-inflammatory cytokines, e.g., IL-1RA, and the control of pro-inflammatory cytokines, e.g., TNF. The mechanisms regulating these disparate immunomodulatory functions of LL-37 are not completely understood. Rho GTPases are GTP-binding proteins that promote fundamental immune functions such as chemokine production and recruitment of leukocytes. However, recent studies have shown that distinct Rho proteins can both negatively and positively regulate inflammation. Therefore, we interrogated the role of Rho GTPases in LL-37-mediated immunomodulation. We demonstrate that LL-37-induced production of chemokines, e.g., GRO-α and IL-8 is largely dependent on Cdc42/Rac1 Rho GTPase, but independent of the Ras pathway. In contrast, LL-37-induced production of the anti-inflammatory cytokine IL-1RA is not dependent on either Cdc42/Rac1 RhoGTPase or Ras GTPase. Functional studies confirmed that LL-37-induced recruitment of leukocytes (monocytes and neutrophils) is also dependent on Cdc42/Rac1 RhoGTPase activity. We demonstrate that Cdc42/Rac1-dependent bioactivity of LL-37 involves G-protein-coupled receptors (GPCR) and JNK mitogen-activated protein kinase (MAPK) signaling, but not p38 or ERK MAPK signaling. We further show that LL-37 specifically enhances the activity of Cdc42 Rho GTPase, and that the knockdown of Cdc42 suppresses LL-37-induced production of chemokines without altering the peptide’s ability to induce IL-1RA. This is the first study to demonstrate the role of Rho GTPases in LL-37-mediated responses. We demonstrate that LL-37 facilitates chemokine production and leukocyte recruitment engaging Cdc42/Rac1 Rho GTPase via GPCR and the JNK MAPK pathway. In contrast, LL-37-mediated anti-inflammatory cytokine IL-1RA production is independent of either Rho or Ras GTPase. The results of this study suggest that Cdc42 Rho GTPase may be the molecular switch that controls the opposing functions of LL-37 in the process of inflammation.
Highlights
The human host defense peptide LL-37 is a 37-amino acid cationic peptide with immunomodulatory functions required for resolution of infections and regulation of inflammation [1,2,3,4,5]
The Ras inhibitor farnesylthiosalicylic acid (FTS) did not suppress either LL-37 or LPS-induced chemokine production (Figure 1C). These results demonstrated that LL-37-induced chemokine mRNA expression and protein production was dependent on Cdc42/Rac1 Rho GTPase, but independent of Ras GTPase
We have demonstrated that LL-37-induced production of chemokine IL-8, which recruits neutrophils is dependent on Cdc42/Rac1 Rho GTPase in macrophage-like THP-1 cells (Figure 1), in human Peripheral Blood-Derived Mononuclear Cells (PBMC) (Figure 4) and Monocyte-Derived Macrophages (MDM) (Figure 5)
Summary
The human host defense peptide LL-37 is a 37-amino acid cationic peptide with immunomodulatory functions required for resolution of infections and regulation of inflammation [1,2,3,4,5]. LL-37 mediates both pro- and anti-inflammatory responses; LL-37 can promote chemokine production, recruitment of leukocytes, differentiation of macrophages and dendritic cells, polarization of T-cells and angiogenesis, all functions classically defined as pro-inflammatory [6,7,8]. LL-37 exhibits antiinflammatory properties such as intervening in toll-like receptor signaling to suppress endotoxin-induced pro-inflammatory cytokines, regulating signaling mechanisms and downstream responses induced in the presence of pro-inflammatory cytokines such as IL-32, and promoting the production of anti-inflammatory cytokines such as interleukin-1-receptor antagonist (IL-1RA) [4, 9, 10]. GPCRs are known to trigger complex signaling networks that involve Rho GTPases and MAPK pathways [12]. Involvement of Rho GTPases in the immunomodulatory functions of LL-37 has not been fully elucidated
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