Indirect effects of immunological tolerance to a regular dietary protein reduce cutaneous scar formation

Summary Oral tolerance refers to the specific inhibition of immune responsiveness to T‐cell‐dependent antigens contacted through the oral route before parenteral immunization. Oral tolerance to one protein does not inhibit immune responses to other unrelated proteins, but parenteral injection of tolerated antigens plus adjuvant into tolerant, but not normal, mice inhibits immune responses to antigens injected concomitantly or soon thereafter. The inhibitory effect triggered by parenteral injection of tolerated proteins is known as bystander suppression or indirect effects of oral tolerance. Intraperitoneal injection of ovalbumin (OVA) plus alum adjuvant in OVA‐tolerant mice soon before skin injury inhibits inflammation and improves cutaneous wound healing. However, as OVA is not a regular component of mouse chow, we tested whether indirect effects could be triggered by zein, the main protein of corn that is regularly present in mouse chow. We show that intraperitoneal injection of a single dose (10 μg) of zein plus alum adjuvant soon before skin injury in mice reduces leucocyte infiltration but increase the number of T cells and the expression of resistin‐like molecule‐α (a marker of alternatively activated macrophages) in the wound bed, increases the expression of transforming growth factor‐β3 in the newly formed epidermis and reduces cutaneous scar formation. These results suggest that indirect effects of oral tolerance triggered by parenteral injection of regular dietary components may be further explored as one alternative way to promote scarless wound healing. Oral tolerance develops after ingestion of regular dietary proteins, like zein. Parenteral re‐exposure to orally tolerated proteins has systemic anti‐inflammatory effects. The parenteral injection of zein soon before skin wounding reduces scarring.