Epithelia and innate immune cells communicate to initiate sterile inflammation

Skin is the largest and the outermost organ of the body that acts as a barrier to external agents. It comprises of an outer epidermis and inner dermis which are separated by a meshwork of proteins and carbohydrates known as the basement membrane (also called the extracellular matrix). To serve the protective functions of the skin, both the epidermis and the dermis harbor different types of immune cells (white blood cells) that protect us from infectious microbes and also aid in repair function upon injury. Broadly, these immune cells are classified as innate and adaptive immune cells. The innate immune cells form the first line of defense that fight infections and activate the adaptive immune cells, the second line of defense, which further promotes clearance of infection.

During tissue damage, increase in the recruitment of immune cells is followed by pain, redness, swelling, and heat in the damaged tissues, a condition termed as inflammation. When this inflammation occurs in the absence of infection, it is considered sterile. While a bulk of research highlights the role of immune cells in different stages of inflammation; the initial events that set up the inflammation are less understood. Macrophages, a type of innate immune cell, are a group of specialized immune cells that can kill microorganisms invading the body as well as heal wounded tissues. They are among the first few immune cells to get recruited at the site of tissue damage and are capable of responding to diverse environmental factors.

In this study, we used a mouse embryonic model for sterile inflammation to unravel the contribution of different compartments of skin (epidermis, dermis, and macrophages) towards initiating a sterile inflammatory cascade. We showed that macrophages are the major immune cells present in the inflamed embryonic skin. They become active and express extracellular matrix remodelling enzymes leading to an exaggerated disorganization of the basement membrane. Consequently, removal of the macrophages reduced disruption of the basement membrane. We then asked what might be regulating this activation state of macrophages. We found that epidermis expresses a protein called cyclooxygenase-2 that causes the epidermis to express danger signals (cytokines and chemokines) that, in turn, influence the macrophages to become active and express basement membrane remodeling enzymes. This suggests that a crosstalk between the epithelia and the macrophage is an initial step in setting up an inflammatory condition in the skin. Taken together, our study provides clues to target the initial events in setting up inflammation and can be used to understand disease progression processes better.