Research examines how early-life microbial exposure trains the immune system to prevent long-term chronic disease

The hygiene hypothesis connects being exposed to microbes early in life with training the immune system to be stronger throughout life. And it argues that limiting exposure to microbes in childhood dysregulates the immune system, causing it to be prone to chronic inflammation and lead to disease outcomes like allergies and asthma later in life. We may not yet have a complete molecular-level understanding of how microbiomes train the immune system for optimal health, but we do know early-life, microbe-immune interactions on barrier surfaces, like a newborn’s skin, have lasting health impacts. And that when healthy microbiomes are absent, it can trigger a trajectory toward inflammation and disease.  

Recent research by Miqdad Dhariwala, PhD, and his group, titled “Commensal-myeloid Crosstalk in Neonatal Skin Regulates Interleukin-1 Signaling and Cutaneous type 17 Inflammation,” was just published in the journal Immunity. The study examines the interactions of myeloid immune cells, which are the primary sensors of microbial presence, with commensal, or friendly, microbes during early-life and its impact on long-term tissue health. Commensal microbes colonize barrier surfaces on or within the human body and benefit from the host environment while also rendering benefits to host health. Dhariwala and his group demonstrate that commensal microbes recruit classical monocytes to neonatal skin and interact with and integrate those signals, playing essential roles in health and immunity. Through a deep examination of the biology of microbes, this research revealed: 

• A deeper understanding of what monocytes are doing early on in life when interacting with microbes, revealing a previously unknown immune regulation role in the neonatal skin. 
• Exposing mice to a rich diversity of microbes and others to an environment stripped of microbes showed monocytes were present and peaked in numbers as early as postnatal day 3 in the skin of the rich environment but absent in the sterile environment. Finding these traditionally inflammatory cells present and in high numbers when a neonate is born healthy was surprising to the group that devised innovative strategies to dissect their biology during early life.   
• Figuring out how monocytes arrive and why led them to deplete those cells only in early life. They used single-cell RNA sequencing across all immune populations to capture the full genetic landscape of immune cells in the skin.  
• Immediately after the depletion of these monocytes, the programming of lymphocytes, the secondary responders of the immune system, began producing the inflammatory cytokine IL-17, which is typically produced in response to injury or bacterial infection.  
• Dhariwala and colleagues revealed that monocytes enter young skin to actually regulate and turn off inflammation, when we used to believe they turned the switch on for inflammation. They also tested adolescent and adult human skin and observed the same patterns in these monocytes.  
• Mice with depleted monocytes in the neonatal window, who are producing large amounts of IL-17, were then exposed to a mouse model of psoriasis, a disease of the skin in which the IL-17 pathway drives disease pathogenesis. Interestingly, they demonstrated that mice where monocytes were depleted, when challenged with psoriasis in adulthood (when monocyte numbers had recovered), were more susceptible to this inflammatory disease.  
• Together, this study demonstrates the importance of early-life programming of immune cells in barrier sites and how critical this is to prevent the onset of chronic inflammatory diseases later in life.  

By demonstrating the unique functionality of monocytes during early life, Dhariwala and his laboratory colleagues at The Ohio State University Wexner Medical Center are determined to reveal the molecular mechanisms that govern microbial training of immune function in neonatal barrier tissues. Dhariwala received the prestigious National Institutes of Health Pathway to Independence Carrer Transition K99/R00 Award, which has helped him launch his independent research program here at Ohio State.