Hematopoietic Stem and Progenitor Cells Locally Produce Neutrophils Necessary To Resolve S. Aureus-Infected Wounds
Authors: Falahee Patrick C , Granick Jennifer L , Dahmubed Delsheen , Simon Scott I 
Published: October 2019

Staphylococcus aureus is a frequent cause of chronic nosocomial skin and soft tissue infections that can spread to muscle, bone and connective tissue. During the normal inflammatory response to infection, a heterogeneous population of circulating and bone marrow (BM)-derived cells are recruited to the site of injury that collectively contributes to host defense and tissue repair. Included among these are polymorphonuclear leukocytes (PMN), which serve a critical role as the first-line of defense in the innate immune response to S. aureus.
Through detection and intervention of the number of PMN accessing the wound in a transgenic mouse model of S. aureus infected skin wounds, we discovered that a subset of hematopoietic stem and progenitor cells (HSPC) that are lineage negative, Sca-1+ and c-kit+ (LSK cells) traffic to the site of infection, where they undergo local granulopoiesis and account for up to 30% of total PMN found within the abscess. Blocking trafficking of LSK revealed that local expansion into PMN is critical for clearance of bacteria and efficient wound closure. To determine if toll like receptor (TLR) signaling contributed to local granulopoiesis, we compared the capacity of multi-potent LSK cells from WT, TLR2-deficient or MyD88-deficient mice transferred into wounds functioned in a similar manner to those trafficking into WT wounds in terms of PMN expansion and resolution of infection. LSK isolated and adoptively transferred from BM of WT mice into WT, TLR2-deficient or MyD88-deficient mice produced equivalent numbers of PMN and contributed to wound resolution. In contrast, LSK derived from TLR2- or MyD88-deficient mice that were transferred into WT wounds produced few PMN, indicating that TLR2 and MyD88 are both necessary for local granulopoiesis in response to S. aureus infection. The signaling pathway involved downstream production of PGE2 that acts in an autocrine manner to signal LSK cell expansion and myeloid proliferation. Local administration of PGE2 to infected wounds of TLR2- or MyD88-deficient mice restored PMN production and rescued resolution of infection in knockout mice.
These findings shed light on a novel innate immune mechanism by which stem and progenitor cells traffic to S. aureus-infected wounds and produce PMN following direct stimulation in a manner dependent on TLR2/MyD88 signaling. Current studies are focused on the process of local granulopoiesis in terms of: The local granulopoietic niche and comparing it with myeloid proliferation in BM; The antibacterial capacity of PMN locally produced versus systemically recruited to the wound; Identification of molecular pathways parallel or downstream of PGE2 that are critical for on demand production of PMN within infection. An overall goal is to strategically manipulate the process of on demand production of PMN to more efficiently battle chronic and persistent infections as may occur in immune compromised patients.

Disclosures:
No relevant conflicts of interest to declare.