Innate immune restoration after major surgery in the elderly: functional adaptation for maintaining immune reactivity

Innate immune memory reflects the capacity of innate immune cells to undergo functional reprogramming after challenges. Given its importance as protective immune mechanism in the elderly, in this study we aimed to characterize the development of protective functional innate memory upon major surgery in elderly patients. In a prospective cohort of 102 elderly patients undergoing major surgery, innate immune reactivity was measured as blood leukocyte response to bacterial LPS one day before surgery and 3 months post-operatively, using free active IL-1β as reactivity index. Based on their response, patients were initially classified into four functional response categories: Normal (n=53), Anergic (n=18), Hyperreactive (n=18), and Inflamed (n=13). Thirty-two circulating biomarkers and 29 clinical parameters were analyzed for association with immune state and trajectory. Three months post-surgery, substantial improvement occurred, with 55% Anergic and 67% Hyperreactive patients reaching immune normalization, although some patients maintained abnormal response and some adopted an abnormal reactivity. Irrespective of trajectory, the post-surgical reactivity index was the result of a re-directioning of the production of inflammatory vs. anti-inflammatory factors, suggestive of the establishment of functional innate immune memory. Among clinical and biochemical variables, age emerged as the only significant predictor of immune trajectory in initially Normal patients, with individuals >75 years showing a higher risk of post-operative anergy. This study suggests for the first time that surgery-related stress could induce a functional cell-intrinsic memory-like immune modulation that improves subsequent immune responsiveness in elderly individuals. Thus, surgery-induced innate memory can be considered as an adaptation mechanism for maintaining/attaining optimal immune functionality. The maladaptive post-operative immune reactivity observed in some individuals stresses the need for future personalized interventions to re-establish the capacity of optimal adaptation.