Innate immune recognition of invading pathogens by pattern-recognition receptors (PRRs) is important to initiate protective immune responses (Medzhitov, 2007; Kawai and Akira, 2011). Yet uncontrolled activation of PRRs by pathogen-associated molecular patterns (PAMPs), such as LPS, can result in unbalanced cytokine production and potentially fatal tissue injury. Neutrophils express multiple PRRs, including the LPS receptor TLR4 (Hayashi et al., 2003), and are typically the first immune cells to be recruited to sites of infection (Kolaczkowska and Kubes, 2013; Mócsai, 2013; Mayadas et al., 2014; Nauseef and Borregaard, 2014). Neutrophils can efficiently kill bacteria through different defense mechanisms (Borregaard, 2010; Kolaczkowska and Kubes, 2013; Mócsai, 2013; Mayadas et al., 2014); however, some neutrophil products may be detrimental to the host, particularly in the context of excessive activation by PAMPs, such as during LPS-induced endotoxemia (Mócsai, 2013; Mayadas et al., 2014; Nauseef and Borregaard, 2014). Indeed, it is generally considered that neutrophils exacerbate the inflammation and tissue damage associated with LPS exposure. Surprisingly, there is a lack of formal evidence to demonstrate this detrimental role for neutrophils. Moreover, systemic inflammation leads to a functionally heterogeneous neutrophil compartment (Pilla y et al., 2010) and, in humans, low-dose LPS exposure induces the appearance of a subset of CD62LdimCD11bhigh neutrophils that can suppress T cell activation ex vivo (Pillay et al., 2012). The latter finding suggests that some neutrophils might possess immunosuppressive functions in the context of endotoxemia. In the present study, we used mouse models to investigate further the role of neutrophils during LPS-induced endotoxemia. There is a paucity of suitable models available to study neutrophil functions in vivo: animals with constitutive neutropenia exhibit other immune abnormalities and are more susceptible to infections (Hock et al., 2003), whereas antibodies used at high doses to deplete neutrophils have known or likely effects on other cell populations (Conlan an d North, 1994; Daley et al., 2008). Therefore, we have devel-neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). to study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model, PMndtr mice, in which injection of diphtheria toxin induces selective neutrophil ablation. using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. this protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment. Blockade or genetic deletion of myeloperoxidase (MPo), a key neutrophil enzyme, significantly increased mortality after LPS challenge, and adoptive transfer experiments confirmed that neutrophil-derived MPo contributes importantly to protection from endotoxemia. our findings imply that, in addition to their well-established antimicrobial properties, neutrophils can contribute to optimal host protection by limiting the extent of endotoxin-induced inflammation in an MPodependent manner.