Sepsis, an overwhelming inflammatory response syndrome secondary to infection, is one of the costliest and deadliest medical conditions worldwide. Neutrophils are classically considered to be essential players in the host defense against invading pathogens. However, several investigations have shown that impairment of neutrophil migration to the site of infection, also referred to as neutrophil paralysis, occurs during severe sepsis, resulting in an inability of the host to contain and eliminate the infection. On the other hand, the neutrophil antibacterial arsenal contributes to tissue damage and the development of organ dysfunction during sepsis. In this review, we provide an overview of the main events in which neutrophils play a beneficial or deleterious role in the outcome of sepsis.

The nervous system is classically organized into sympathetic and parasympathetic systems acting in opposition to maintain physiological homeostasis. Here, we report that both systems converge in the activation of β2‐adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either β2‐knockout or lymphocyte‐deficient nude mice. Unlike typical suppressor CD25 ⁺ cells, the transfer of CD4 ⁺ CD25 ⁻ regulatory lymphocytes reestablishes the anti‐inflammatory potential of the vagus nerve and β2‐agonists to control inflammation in both β2‐knockout and nude mice. β2‐Agonists inhibit cytokine production in splenocytes (IC ₅₀ ~1 μM) and prevent systemic inflammation in wild‐type but not in β2‐knockout mice. β2‐Agonists rescue wild‐type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti‐inflammatory potential of β2‐agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in β2‐knockout mice. These results indicate that β2‐adrenoceptors in regulatory lymphocytes are critical for the anti‐inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.—Vida, G., Peña, G., Kanashiro, A., del Rocio Thompson‐Bonilla, M., Palange, D., Deitch, E. A., Ulloa, L. β2‐Adrenore‐ceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system. FASEB J. 25, 4476–4485 (2011). www.fasebj.org