MyD88 in Macrophages Is Critical for Abscess Resolution in Staphylococcal Skin Infection

Abstract

When Staphylococcus aureus penetrates the epidermis and reaches the dermis, polymorphonuclear leukocytes (PMLs) accumulate and an abscess is formed. However, the molecular mechanisms that orchestrate initiation and termination of inflammation in skin infection are incompletely understood. In human myeloid differentiation primary response gene 88 (MyD88) deficiency, staphylococcal skin and soft tissue infections are a leading and potentially life-threatening problem. In this study, we found that MyD88-dependent sensing of S. aureus by dermal macrophages (Mϕ) contributes to both timely escalation and termination of PML-mediated inflammation in a mouse model of staphylococcal skin infection. Mϕs were key to recruit PML within hours in response to staphylococci, irrespective of bacterial viability. In contrast with bone marrow–derived Mϕs, dermal Mϕs did not require UNC-93B or TLR2 for activation. Moreover, PMLs, once recruited, were highly activated in an MyD88-independent fashion, yet failed to clear the infection if Mϕs were missing or functionally impaired. In normal mice, clearance of the infection and contraction of the PML infiltrate were accompanied by expansion of resident Mϕs in a CCR2-dependent fashion. Thus, whereas monocytes were dispensable for the early immune response to staphylococci, they contributed to Mϕ renewal after the infection was overcome. Taken together, MyD88-dependent sensing of staphylococci by resident dermal Mϕs is key for a rapid and balanced immune response, and PMLs are dependent on intact Mϕ for full function. Renewal of resident Mϕs requires both local control of bacteria and inflammatory monocytes entering the skin.

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

“…Mouse skin was infected as previously described (3). Briefly, bacteria were grown to mid-log phase, washed with PBS twice, and resuspended in PBS at ∼3 3 10 8 CFU/ml.…”

“…Proper TLR function in resident immune cells, especially tissue macrophages (MFs), is required to hold potentially virulent bacteria in check at mucocutaneous sites (2)(3)(4). Yet, the policing function of MFs, which stabilizes surface niches for colonizing bacteria, and the dangerous hyperinflammatory response of myeloid cells during bacterial spread result from similar interaction principals between bacterial effectors and TLRs.…”

Keigairengyoto, a traditional Japanese medicine, promotes bacterial clearance by activating innate immune cells in mouse cutaneous infection models

“…The procedure was performed according to the previous report with a minor modification [7] . The ear was cut into nine pieces, followed by enzyma tic digestion in PBS containing 0.45 mg/ mL dispase I (Roche Diagnostics, Indianapolis, IN, USA), 2 mg/mL collagenase II (Sigma-Aldrich), and 0.32 mg/mL DNase I (Sigma-Aldrich) for 2 h while shaking at 37 °C.…”

“…Macrophages have characteristics of diversity and plasticity in cell differentiation, therefore playing roles in inflammation and tissue repair and regeneration [6] . Resident dermal macrophages orchestrate the initiation and termination of immune response in skin infection [7] . A deficiency of macrophage function fails in the timely recruitment of neutrophils to the site of infection and delays bacterial clearance [7] .…”

“…Resident dermal macrophages orchestrate the initiation and termination of immune response in skin infection [7] . A deficiency of macrophage function fails in the timely recruitment of neutrophils to the site of infection and delays bacterial clearance [7] . These lines indicate that resident dermal macrophages play important roles in the initial detection of skin-infiltrating bacteria and the activation of neutrophils.…”