A Novel Lipopeptide from Skin Commensal Activates TLR2/CD36-p38 MAPK Signaling to Increase Antibacterial Defense against Bacterial Infection

Abstract

Staphylococcus epidermidis (S.epidermidis) plays important protective roles by directly producing or by stimulating hosts to produce antimicrobial peptides (AMPs) against pathogenic infections. Although several AMPs from S.epidermidis have been identified, molecules that stimulate hosts to produce AMPs remain largly unknown. Here we demonstrate that a new lipopeptide (named LP01) purified from S.epidermidis culture media has a unique structure with heneicosanoic acid (21 carbons) binding to lysine11 of a peptide chain. In vitro LP01 increased the expression of β-defensin 2(hBD2) and hBD3 in neonatal human epidermal keratinocytes(NHEK), leading to increased capacity of cell lysates to inhibit the growth of S.aureus. In vivo LP01 induced the expression of mouse β-defensin 4(mBD4) to decrease the survival of local S.aureus in skin and systemic S.aureus survival in liver. The induction of beta-defensins by LP01 was dependent on TLR2 as Tlr2-deficient mice had decreased mBD4. Furthermore, knockdown of CD36 decreased the expression of hBD2 and hBD3, and p38 MAPK inhibitor significantly inhibited the expression of hBDs induced by LP01.Taken together, these findings demonstrate that lipopeptide LP01 from normal commensal S.epidermidis increases antimicrobial peptide hBD2 and hBD3 expression via the activation of TLR2/CD36-p38 MAPK, thus enhancing antimicrobial defense against pathogenic infections.

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

“…For example, S. epidermidis is able to dampen inflammatory processes after skin wounding [5] and it secretes antimicrobial factors, which restrict the growth of other competing microbes [3,6]. In addition, S. epidermidis directly induces the expression of antimicrobial peptides in keratinocytes [7][8][9] or indirectly via S. epidermidis-spe-F.R. and M.S.…”

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

“…2A, both Itch 2/2 and Ndfip1 2/2 macrophages secreted elevated levels of proinflammatory cytokines compared with WT macrophages. To confirm that the elevated proinflammatory cytokine expression was through the P6-TLR2 pathway (13), we used a TLR2 inhibitor, OxPAPC (29,30). We found that OxPAPC significantly inhibited P6-induced proinflammatory cytokines in Itch 2/2 and Ndfip1 2/2 cells (Fig.…”

Activation of p38 and Erk Mitogen-Activated Protein Kinases Signaling in Ocular Rosacea

“…14,22 These receptors are well known to promote p38 and Erk activation, 23,24 and these pathways have been shown to mediate multiple keratinocyte responses. For example, TLR2-mediated p38 and Erk activation was required for the inflammatory and antimicrobial responses of keratinocytes challenged with streptococcal M1 protein, 25 Staphylococcus epidermidis LP01 lipopeptide, 26 or Candida albicans phospholipomannan. 27 Moreover, the TLR4/p38 signaling axis is essential for normal cutaneous wound healing, 28 and expression of TLR2 and TLR4 was found to be altered in atopic dermatitis, contact dermatitis, and psoriasis.…”